This is an ongoing project in clinical research in breast cancer with the long-term goal of improving hormonal treatment of breast cancer. The principal imaging tool for this Project will continue to be PET ER imaging using [F-18]-fluoroestradiol (FES), and the proposed studies follow directly from our work in the current funding period showing heterogeneous ER expression in breast tumors. We will now test approaches to evaluate factors affecting response. The focus of our proposed studies will be patients with recurrent or metastatic breast cancer from an ER+ primary tumor who are being considered for treatment with aromatase inhibitors, the hormonal therapy of choice for this patient population. In this group of patients, where biopsy is difficult because of multiple or inaccessible sites of disease, imaging can identify therapeutic targets and play a significant role in directing therapy. Our specific aims are to (1) determine the ability of FES PET imaging to predict patient's response to hormonal therapy, (2) determine the early response to hormonal therapy by measuring the change in receptor occupancy and tumor proliferation early in the course of treatment, and (3) determine the relationship between ER expression and the abnormal expression of other growth factor receptors, specifically HER2 and EGFR, and their relationship to response to hormonal therapy. These studies will lead directly to clinical paradigms using PET imaging data with tumor-specific receptor ligands to make individualized choices of therapy in patients. The studies will also identify which mechanisms of resistance to hormonal therapy are clinically important and help direct efforts to overcome resistance to hormonal treatment of breast cancer.